Absence of apolipoprotein E protects mice from cerebral malaria

Cerebral malaria is a neurological complication of malaria that claims the life of millions of people every year, particularly those of children under the age of five1. It is mainly characterized by coma and is fatal if left untreated, making it the leading cause of malaria-related death. Pathology is caused by multiple factors, particularly the sequestration of parasitized red blood cells (RBCs) and leukocytes within the brain, which leads to the hallmark disruption of the blood-brain barrier (BBB)2,3. Cerebral malaria is currently treated with anti-malarial drugs, such as quinine/quinidine or artemisnin derivatives4. These drugs are very effective at eliminating the parasite, but the anti-malarial treatment needs to be initiated during the early stages of the disease. Even with the timely administration of anti-malarial drugs, 20–30% of patients still succumb to cerebral malaria5. Once the disease has progressed to severe malaria, patients will receive adjunctive treatments in conjunction with anti-malarial drugs, in an attempt to lessen the associated pathophysiological processes5. However, only a few adjunctive therapies have shown potential in reducing morbidity4,5. Therefore, there is a growing need for the identification of novel mechanistic players to develop effective adjunctive therapies. Based on this, we previously utilized a proteomic approach to discover unique biomarkers in the sera of malaria patients that could potentially be used as therapeutic targets6. One of the identified biomarkers was apolipoprotein A (ApoE), a 34 kDa glycoprotein that is produced by hepatic parenchymal cells and astrocytes, and that is abundant in the plasma6,7. ApoE is known to influence the onset and the rate of progression of several neurological disorders such as Alzheimer’s disease, cerebral amyloid angiopathy and traumatic brain injury7,8,9. In Alzheimer’s disease, ApoE was shown to modulate pathology by altering the aggregation and clearance of amyloid-β from the brain, and by modifying neuroinflammation and brain lipid transport10,11. Furthermore, ApoE has also been demonstrated to play a role in malaria infection. It was reported that ApoE is able to inhibit the infection of liver cells by malaria sporozoites by interacting with heparan sulfate proteoglycans receptors, which are utilized by the parasite to enter the host hepatocytes12. Additionally, ApoE is also able to interact with parasite surface proteins, particularly the early transcribed membrane proteins13. Notably, APOE polymorphisms have been associated with an increased risk of developing severe malaria13,14. Therefore, we were interested in elucidating whether ApoE played a role in the development of cerebral malaria pathology. Herein we report that ApoE−/− mice are significantly protected against cerebral malaria, and that pharmacological inhibition of ApoE using heparin octasaccharide (OCTA) could represent a new avenue in the development of adjunctive therapies for cerebral malaria.